(a) Field of the Invention
The present invention relates to a method and a pharmaceutical composition for treating the symptoms associated to a neurodegenerative disease such as Parkinson's disease. The method and the pharmaceutical composition use a combination of a therapeutically effective amount of at least one of DHEA or DHEA-S in combination with a therapeutically effective amount of a dopamine precursor. The present invention also related to the use of at least one of DHEA or DHEA-S in combination with a therapeutically effective amount of a dopamine precursor for treating a neurodegenerative disease or to manufacture a medicament.
(b) Description of Prior Art
Parkinson's disease is attributable to a loss of dopamine in the brain caused by dopamine-producing nerve cells of the substantia nigra that begin to decrease in number and to the chemical break down of the remaining dopamine in the synapses. The deficient level of dopamine in Parkinson's patients throws off the normal dopamine/acetylcholine balance, since the level of acetylcholine remains normal. The dopamine/acetylcholine imbalance results in a lack of coordination of movements, tremors, stiff muscles and joints, and/or difficulty moving.
Unfortunately, no cure for Parkinson's disease is known thus far despite many attempts to stop the loss of dopamine-producing nerve cells or to restore those lost in the course of the disease. The only effective treatments available to Parkinson's patients are palliative therapies, which consist in helping patients to manage their slow decline by replacing or simulating the effect of the dopamine to compensate for the dopamine deficiency, slow down or reduce the ongoing loss of dopamine, or balance the level of acetylcholine with the level of dopamine in the brain.
Among the existing therapies for Parkinson's disease symptoms, levodopa, (L-3,4-dihydroxyphenylalanine) is one of the most effective medication for controlling the stiffness, tremors, spasms, and poor muscle control of Parkinson's disease patients. Levodopa is a dopamine precursor which is transported to the brain, picked up by the nerve cells that produce dopamine, converted into dopamine and further used as a neurotransmitter. Use of levodopa for dopamine replacement therapy can however constitute an effective mean to control the symptoms of Parkinson's disease for a limited period. Indeed, as the loss of dopamine-producing nerve cells continues, symptoms continue to worsen and consequently, the dose of levodopa administered to patients has to be increased. Over time, continual increases in the levodopa dose may eventually lead to the development of side effects which in many cases are so important that it becomes impossible to increase the dose of levodopa any higher.
To avoid levodopa-associated peripheral side effects, prior art reports the combination of that dopamine precursor with different compounds. For example, addition of carbidopa to levodopa (Sinemet®) delays the conversion of levodopa into dopamine until it reaches the brain, contributes to reduce the amount of levodopa needs and therefore preventing or diminishing some of the side effects that often accompany levodopa therapy. Combination of levodopa to benserazide (Prolopa®) prevents the conversion of levodopa into dopamine in the body, with the exception of brain, and therefore prevents side effects such as nausea and palpitations. However, these combined drugs are less likely effective to prevent motor complications such as wearing-off, on-off and dyskinesia, which are major drawbacks associated to dopamine-replacement therapies. In addition, these drug combinations are ineffective to prevent levodopa response fluctuations and the shortening of the effect of levodopa through the years of treatment.
One of the avenue envisioned in the recent years for the treatment of in neurodegenerative diseases such as Alzheimer and Parkinson (M. Cyr et al., (2000), Curr. Pharm. Des. 6, 1287-312) relates to the use of sex steroids. Indeed, estrogens and androgens (sex steroids) exert profound effects on brain differentiation, neural plasticity and central neurotransmission during development (M. Kawata, (1995), Neurosci. Res. 24, 1-46; B. S. McEwen and S. E. Alves, (1999), Endocr. Rev. 20, 279-307). In adult men and women, accumulating evidence supports a modulatory role of these steroids in the brain (B. B. Sherwin, (1997), Neurology 48, S21-6) and their prime importance in the normal maintenance of brain function during aging (J. W. Simpkins et al., (1994), Neurobiol. Aging 15, S195-7).
The role of sex steroids in Parkinson's disease is also illustrated by a greater prevalence and incidence of Parkinson's disease in men than in women (M. Baldereschi et al., (2000). Neurology 55, 1358-63; G. F. Wooten et al., (2004) J. Neurol. Neurosurg. Psychiatry 75, 637-639). Gender differences on evolution of symptoms and responses to levodopa treatment are also reported (K. E. Lyons et al., (1998). Clin. Neuropharmacol. 21, 118-21). Modulation of dopaminergic action pathway by estrogens is now well established. Symptoms of Parkinson's disease and levodopa-induced dyskinesias were also shown to be modulated by estrogens (T. Di Paolo, (1994). Rev. Neurosci. 5, 27-41).
Dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S) are sex steroid precursors of both estradiol and testosterone. These steroid precursors are also considered as being neurosteroids, since they have been shown to be synthesized in the brain (I. H. Zwain and S. S. C. Yen, (1999). Endocrinology 140, 880-887). Studies undergone to determine a role of DHEA and DHEA-S in Parkinson's disease suggested few time ago no particular function of these sex steroid precursors in Parkinson's disease, since no significant difference in cerebrospinal fluid DHEA and DHEA-S were found between Parkinson's disease patients and age-matched controls (T. Azuma et al., (1993). J. Neurol. Sci. 120, 87-92).
More recent evidences however report a role pf DHEA in Parkinson's disease. For example, international patent application published under number WO 01/55692 disclose methods and kits whereby the onset of neuropathology, such as Parkinson's disease, is detected by changes in the normal levels of neurosteroids, and particularly DHEA and its metabolic precursors, in the brain and serum. Modulation of dopaminergic activity by DHEA was also shown, but to a lower extent than estrogens. Moreover, DHEA was shown to have a protective role, protecting animals against a dopamine depletion caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (M. D'Astous et al., (2003). Synapse 47, 10-14).
Published U.S. patent application 2002/0182196 discloses a nutritional supplement composition for normalizing impaired or deteriorating neurological function in humans, such as those occurring in Parkinson's disease. This composition comprises at least one agent for normalizing or maintaining normal neurotransmitter function in the body, at least one agent for down-regulating cortisol action and several others components. Particularly, this composition may comprise DHEA for which action is limited to cortisol action modulation.
International patent application published under number WO 99/43329 discloses a composition for treatment of a human body comprises a combination of at least one hormone, at least one amino acid, at least one enzyme and/or vitamin, and at least one mineral. The hormone of the composition comprises DHEA and can be used in the treatment of the symptoms associated to Parkinson's disease.
Although DHEA and DHEA-S now seem to play a role in Parkinson's disease, many important side effects are associated to the administration of high doses of DHEA or DHEA-S. For example, acne, increased scalp itching, menstrual irregularities, irritability, restlessness, heart palpitations and scalp hair loss are associated with a DHEA increase in the body. Therefore, it is unlikely that Parkinson's disease therapies relying only on DHEA administration would be successful. Therefore, it would be highly desirable to be provided with a method that conjugates the effect of both DHEA and levodopa.